The MAP kinase negative regulator DUSP2 (dual specificity phosphatase 2) is controlled by oncogenic microRNA cluster miR-17-92, miR-106a-363 and miR-106b-25.

Abstract

Background: Aberrant changes in protein phosphorylation are a hallmark of cancer, often leading to hyperactivation of signalling pathways such as the mitogen activated protein kinase (MAPK) pathway. Although kinase inhibitors are successfully used in certain clinical indications, drug resistance remains a challenge, and alternative approaches to control phosphorylation-dependent oncogenic signalling are increasingly being considered. These include the modulation of negative regulators of oncogenic signalling pathways. The dual-specificity phosphatase 2 (DUSP2) is one of the essential negative regulators for the MAPK pathway, providing tight and efficient control of MAPKs under physiological conditions. However, in oncogenic contexts, negative feedback regulation is often impaired and the mechanisms controlling DUSP2 expression and function remain largely elusive. The aim of the present study was to investigate whether microRNA-mediated regulation of DUSP2 could contribute to an impairment of negative feedback regulation in cancer.

Methods: A combination of in silico target prediction, integrative analysis of pan-cancer microRNA and DUSP2 mRNA expression data as well as a literature search was applied to identify microRNAs potentially regulating DUSP2 expression in cancer context. Predicted interactions of microRNAs with the DUSP2 3'UTR were verified using reporter gene assays and functionally validated in a lymphoma cell model.

Results: A comprehensive analysis of microRNA and DUSP2 mRNA expression data across 32 cancer types revealed significant inverse correlations between oncogenic microRNA clusters (miR-17-92, miR-106a-363, and miR-106b-25 cluster) and DUSP2 expression in various cancer types. Reporter gene assay analysis confirmed the interaction of miR-17-5p, miR-20a-5p, miR-20b-5p, miR-29b-3p, miR-93-5p, miR-106b-5p, miR-122-5p, miR-340-5p, miR-520a-3p, and miR-520c-3p with the DUSP2 mRNA 3'UTR. Furthermore, treatment of the lymphoma cell line WSU-DLCL2 with microRNA inhibitors for miR-17-5p, miR-20b-5p, or miR-106b-5p resulted in increased DUSP2 mRNA levels.

Conclusion: The results of this study indicate that microRNA-mediated regulation of DUSP2 in hematologic and solid cancers appears to be a plausible mechanism that contributes to the dysregulation of MAP kinase signaling pathways in cancer by impairing negative feedback regulation. The data provide a solid foundation for future studies to investigate the consequences of regulation of DUSP function in cancer in more depth.